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Lipoprotein immunogenetics and atherosclerosis.

The discovery of the first human lipoprotein polymorphism by Allison and Blumberg [Lancet i:634-637, 1961] and the availability of alloimmune sera stimulated us to begin immunogenetic studies on swine in search of lipoprotein diversity and its relationship to biological functions. We found considerable lipoprotein polymorphism, complexity, and heterogeneity in this species. These results and the correlation between immunogenetically defined lipoprotein type and arterial lipidosis in swine, fed a high fat diet, are discussed. Immunogenetic studies of lipoproteins, initiated more recently in rhesus monkeys, will be reviewed also. Preliminary data show similarities between these two species with regard to polymorphism, complexity, phenotypic expression of lipoprotein genes and, most importantly, their serological relationship to human lipoproteins. We also note immunogenetic studies on lipoproteins done by other investigators, or in other species. Brief remarks on implications of the lipoproteins in atherosclerosis, their general classification, immunological properties, and immunological methods used in their study precede the immunogenetic presentation.

Animals

Towards a unified theory for immunogenetic systems. Some selected properties of ABC- and AB-D reaction patterns generated by S3 and T3 universes.

The principles of a radically new unified theory and a unified but fundamentally theory-invariant classification system are described and exemplified for immunogenetic systems. The classification system permits a differentiation of immunogenetic systems into 15 qualitatively distinct classes with quantitative subsets when tested against two reagents. It can easily be expanded into a n-reagent taxonomy. The theory logically explains a set of selected and previously more or less "unexplainable" properties and their (even more unexplainable and probably previously unnoticed) associations in two main classes of immunogenetic systems, the ABC- and AB-D systems. The associated properties discussed are the presence (+) or absence (-) of: 1. antithetical alleles; 2. dosage effects; 3. inherited "strong" and "weak" antigens; 4. "silent" or "amorphous" genes. In ABC- systems, properties 1 and 2 are present while 3 and 4 are absent or extremely rare (i.e. 1+2+3-4-). In AB-D systems, properties 1 and 2 are absent while 3 and 4 are present (i.e. 1-2-3+4+). Through the design of hypothetical immunogenetic universes (HIU), these property associations are shown to be produced by the contemporary (simple-complex) framework-dependent transformations of experimental observables/matrix facts and not by any corresponding associated properties present in the input HIU in themselves.

ABO Blood-Group System

Morphological reaction in transplanted small intestines using immunogenetically defined rat strain combinations.

From the inbred rat stains F344, LEW and Brown-Norway (BN), the following combinations were formed: syngeneic (LEW--LEW), weakly allogeneic (F344--LEW) and strongly allogeneic (BN--LEW). A small intestine segment was transplanted using the by-pass technique; after 10 days the graft was removed and histologically investigated. The strongest rejection was found in the lymphatic tissue and the epithelium of the small intestinal transplant. The immunogenetical difference is significant for the survival of the graft: the greater the immunogenetical difference between donor and host, the more severe the morphologically demonstrable rejection reaction.

Animals

Immunogenetic diversity of two South Asian cohorts: From Pakistan and India.

Having critical roles in immune defense and reproduction, killer cell immunoglobulin-like receptors (KIR) and their human leukocyte antigen (HLA) class I ligands are encoded by the most polymorphic regions in the human genome. South Asia comprises over one quarter of the global population and harbors rich genomic diversity. Limiting our understanding of population-specific variation and disease susceptibility, high-resolution immunogenetic studies of South Asian ancestry individuals are lacking. Here, we characterize KIR and HLA class I diversity in two South Asian cohorts: sampling an urban population from Karachi, Pakistan (n = 79), and a Dravidian-speaking Yadav population from southern India (n = 70). Targeted sequencing identified 151 distinct KIR alleles across 13 genes, including 11 previously uncharacterized allotypes. Over 75% of the genotypes were KIR-Bx. We identified 98 HLA class I alleles and extensive haplotypic diversity, with all major KIR binding motifs represented, and a mean of seven potential inhibitory KIR-HLA interactions per individual (6.6 in Karachi, 7.4 in Yadav). Together, these results demonstrate substantial immunogenetic diversity and population-specific KIR and HLA variation within the two studied cohorts. This study expands knowledge of KIR and HLA diversity and offers a framework for further evolutionary and disease-focused in South Asia.

Humans

Immunogenetic study on the polymorphism of serum alpha2-lipoproteins in mink. II. Identification of allotypes Lpm-7 and Lpm-8 and genetic control of seven markers of the Lpm system.

By means of alloimmunization of mink, two new antigens, Lpm-7 and Lpm-8, were detected in their sera. Lpm-7 and Lpm-8 allospecificities were referred to a very high density alpha2-lipoprotein (Lpm) by the following criteria: histochemical tests, immunoelectrophoresis, preparative ultracentrifugation, and coalescence of alloprecipitates with heteroprecipitates in double diffusion tests. Genetic analysis indicated that Lpm-7 and Lpm-8, together with the earlier described Lpm-1, Lpm-2, Lpm-3, Lpm-4, and Lpm-5, share a common immunogenetic system. Polymorphism for the seven markers is conditioned by the genetic units Lpm8, Lpm4, Lpm4,8, Lpm4,7, Lpm3,4,8, Lpm1,8, Lpm1,2,7, and Lpm2,4,5,7, which behave as alleles. Of these units, the latter six are probably haploid sets of closely linked genes.

Alleles

Chlamydia trachomatis incidence in relation to vaginal microbiota dynamics, immunogenetics and exposures in a cohort of young student women in France.

BACKGROUND: Given the potential role of the vaginal microbiota in the acquisition of Chlamydia trachomatis infections, we aim to investigate its contribution together with immunogenetics and epidemiological exposures to the incidence of C. trachomatis in young women. METHODS: This study involved 313 female students aged 18-24 years from the i-Predict prevention trial in France. Participants provided four self-collected vaginal samples and filled four self-administered questionnaires every 6 months for 18 months. C. trachomatis-positive participants and negative controls with complete follow-up were selected for this analysis and submitted to chlamydia testing and to vaginal microbiota characterization using 16S rRNA amplicon sequencing. Thirteen human single nucleotide polymorphisms (SNPs) related to C. trachomatis susceptibility and severity were also assessed. RESULTS: Compared to 260 non-infected participants, Gardnerella spp., Fannyhessea vaginae and Prevotella timonensis were more abundant in C. trachomatis-incident participants (n=24) before infection. Having a CST IV at the preceding sample compared to a CST I (3.56 [1.08-11.70], p=0.037) was associated with increased risk of C. trachomatis acquisition, as well as having had multiple concomitant partners in the last 6 months (4.33 [1.19-15.72], p=0.028). Lifetime condom use was associated with decreased incidence (OR 0.38 [0.16-0.94], p=0.037). None of the tested human SNPs was associated with C. trachomatis infection. CONCLUSIONS: In this low-risk for C. trachomatis population, having a CST IV-AB vaginal microbiota and associated bacterial anaerobes was a risk factor for C. trachomatis acquisition after adjustment for other exposures. Condom use remains one of the main tools to prevent incidence.

C. trachomatis

Studies on the antigenicity of vital allogeneic valve leaflet transplants in immunogenetically controlled strain combinations.

The use of defined inbred strains of rats enables reproducible experimentation on the antigenicity of heart valve leaflet transplantation. The inbred strains CAP, F344, and LEW were used as syngeneic, weakly allogeneic (RT-1-identical) and strongly allogeneic (RT-1-incompatible) strain combinations. After heart valve leaflet transplantation, humoral and cell-mediated immune responses were investigated. The results were: (1) Allogeneic heart valve leaflets are antigenic. (2) Just one heart valve leaflet, applied intravascularly induces sensitization of the recipient. (3) In the weakly allogeneic system, sensitization is only revealed by donor-specific skin transplants, while in the strongly allogeneic group, sensitization is demonstrated humorally as well. (4) The greater the immunogenetical difference, the sooner sensitization appears. In the strongly allogeneic system, skin transplants were rejected as "white grafts".

Animals

Host immunogenetic variation and gut microbiome functionality in a wild vertebrate population.

BACKGROUND: The gut microbiome (GM) -important for host health and survival- is partially shaped by host immunogenetics. However, to date, no study has investigated the influence of host Major Histocompatibility Complex (MHC) genes on gut microbiome functionality in a wild population. Here we use a natural population of the Seychelles warbler (Acrocephalus sechellensis) to assess the effects of MHC genes on GM taxonomy and functionality using shotgun metagenomics. RESULTS: Our results show that taxonomic GM composition was associated with MHC-II diversity and the presence of one specific MHC-I allele (Ase-ua 7). Specifically, MHC-II diversity was associated with decreased Lactococcus lactis and increased Staphylococcus lloydii abundance, while Ase-ua 7 was linked to reduced Enterococcus casselifavus and Gordonia sp OPL2 but increased Escherichia coli and Vulcaniibacterium thermophilum. These taxonomic changes may reflect differences in MHC-mediated microbial recognition. In contrast, functional GM composition was significantly associated with increasing individual MHC-I diversity but not MHC-II diversity. In particular, increasing MHC-I diversity was associated with an increased prevalence of microbial defence genes but a reduced prevalence of microbial metabolism genes. Analysis also revealed that functional GM networks were more fragmented in high compared to low MHC-I diversity hosts. CONCLUSION: These results suggest that MHC variation (particularly at MHC-I) plays an important role in shaping both the taxonomy and function of the GM in wild vertebrates. In the Seychelles warbler, this results in trade-offs whereby there is an increase in microbial defence and a reduction in GM metabolic potential in individuals with higher MHC-I diversity. Thus, this work sheds light on the possible costs and benefits of maintaining a healthy microbiome, which is essential for understanding how the GM and immune system co-evolve. Video Abstract.

Animals

Immunogenetic determinants of familial acute lymphocytic leukemia.

Acute lymphocytic leukemia developed almost simultaneously in two adolescent brothers, and another brother and both parents had rheumatoid arthritis. Laboratory studies uncovered no evidence for an underlying immunodeficiency state in the family. Immunogenetic evaluation showed the leukemic siblings to be HLA- and mixed-leukocyte-culture identical and homozygous for a recessively inherited locus dictating the presence of antigens on the surface of B-cells. This Ia antigen, as detected by sera from mothers of leukemic children, appeared to be mapped within the major histocompatibility region and may be a human analogue to murine immune-response antigens associated with susceptibility to leukemia.

Adolescent

Chronic Lyme arthritis. Clinical and immunogenetic differentiation from rheumatoid arthritis.

Ten patients with Lyme arthritis have developed chronic involvement of one or both knees. Lyme arthritis was diagnosed by onset with erythema chronicum migrans (six patients); residence in Lyme, Connecticut (eight); seasonal onset in summer and early fall (nine); early periods of short recurrent attacks (nine); absence of rheumatoid factor (nine); and absence of symmetrical polyarthritis, morning stiffness, subcutaneous nodules, or antinuclear antibodies (in all). Five patients had synovectomies; pannus formation and underlying cartilage erosion were present in all. Seven of the 10 patients had the same B-cell alloantigen, DRw2 (frequency in normal control subjects, 22% [P less than 0.005]), but did not have an increased frequency of the alloantigens associated with rheumatoid arthritis. Chronic Lyme arthritis, the result of an apparent tick-transmitted infection, resembles rheumatoid arthritis pathologically but generally differs from it in both prearticular and immunogenetic characteristics.

Adolescent

Cross-reactivity with mouse antigens in the ferritin immunogenetic (IR-gene) system.

Structural similarity between antigens and self molecules could be responsible for low antibody responses in different immunogenetic (IR-gene) systems. B10.M and B10.D2 strains are high responders, whilst A. Thy-1-1 mice are low responders, following primary immunization with ferritin in saline. Cross-reactivity between mouse-self antigens and ferritin was tested by antigen excess and radioimmunoassay techniques, using cells obtained from normal, unimmunized high- and low-responder mice, to compete for specific antibody. Low-responder A.Thy-1-1 mouse cells consistently displaced more anti-ferritin antibodies than did high-responder B10.M and B10.D2 mouse cells at varying antibody and cell concentrations and these differences were statistically significant (P less than 0.001). It is suggested that the responder status of different strains of mice, following primary immunization with ferritin in saline, could be explained by the degree of cross-activity between self determinants and antigen, such that low responders cross-react to a greater degree with the test antigen than do high-responder mice. A similar mechanism of cross-reactivity could operate in the pathogenesis of HLA-linked diseases.

Animals

HLA and other immunogenetic approaches to the study of diseases in man.

We have attempted to focus on several areas that can be practically explored to elucidate the mechanisms accounting for the polymorphism of the human major histocompatibility complex and attendent disease predispositions. In addition to widespread serologic HLA typing of specific populations, diseases, and families, it is important to improve discriminating methods for expoloration of other areas of the HLA supergene, especially those involved in specific immune responsiveness. It may also be necessary to take into account possible modulating effects of the MHC on other recognized human genes. Application of these improved methods to the study of infertile couples, recognized genetic syndromes, and human malignancies may assist in unraveling the immunogenetic enigma of these diseases.

Allergy and Immunology

Suppression of antibody responses in allogeneic mice by products of lymphoid tissue. II. Lack of antigenic specificity and immunogenetic requirements of allogeneic suppressive factor (ASF).

Mice were irradiated, infused with thymocytes and immunized with a variety of antigens, i.e., sheep or horse red blood cells (SRBC or HRBC), diphtheria toxoid (DT) or bovine gamma-globulin (BGG). The spleen cells (T.Spleen cells) were harvested 5 days later and cellfree extracts were prepared. The extracts contained an allogeneic suppressive factor (ASF) that was capable of inhibiting IgM antibody responses of allogeneic or semi-allogeneic unirradiated mice. ASF had to be injected within 24 hr of immunization to be effective and a single injection delayed, rather than abolished, the antibody response at the cellular level. However, daily injections of ASF resulted in persistent suppression of antibody response. ASF activity was antigen nonspecific, i.e., the antigen used to stimulate ASF production did not have to be the same as the antigen used to test for ASF activity. C3H T.Spleen extracts were even immunosuppressive when prepared by exposure to C3BF1 alloantigens only; such extracts suppressed antibody responses of C3BF1 and DBA/2 mice. C3H ASF was removed from extracts after incubation with C3BF1 spleen cells but not after incubation with C3H spleen cells. C3BF1 spleen cells which had been preincubated with C3H ASF were unable to generate antibody-forming cells upon transfer to irradiated C3BF1 host mice. This suggests that the ASF molecule may be or include receptors for alloantigens. The immunogenetic requirements for ASF activity were evaluated by injecting extracts from C3H, C57BL, C3BF and BALB/c T.Spleen cells into C3H, CBA, C57BL, BALB/c, DBA/2, A or C3H.A recipient mice. All extracts tested had ASF activity. However, all allogeneic recipients were not suppressed by the extract material. The suppressive activity of ASF seemed to require two (or more) antigenic differences between donors and recipients of extract material, an H-2K or I antigen difference and a second antigen difference, possibility Ig-1. In the limited numbers of strain combinations tested, T.Spleen extracts suppressed IgM antibody response only if exposed to H-2 and Ig-1 antigens, e.g., BALB/c (H-2d, Ig-1a) ASF suppressed A (H-2a, Ig-1e) but not C3H.A (H-2a, Ig-1a) or DBA/2 (H-2d, Ig-1c). Separate ASF molecules may react with separate antigens on the cell surface, i.e., with H-2 and gammaG2a. Alternatively, one ASF molecule may react with two structurally associated antigens. If the latter is correct, it is conceivable that the beta2-microglobulin which is non-covalently linked to the major component of H-2 molecules expresses allotypic antigens coded for by Ig-1 and beta2-microglobulin is one of the antigens recognized by ASF.

Animals

Immunogenetic aspects of allotransplantation.

It now appears unequivocal that three markers exist in a linkage group in chromosome 6 of man: HLA-A, HLA-B and PGM3 (Fig. 1.) Tentatively, two other HLA loci and one Ir gene have been mapped close to HLA-B. The probable map order is HLA-A - HLA-C - HLA-B - HLA-D - Ir. The biological functions of these loci are unknown. However, HLA-A, B and C are important in allograft rejection. Other closely linked loci (HDR, CML) appear to be important in the first events of the allograft rejection (first set) and in generation of killer cells. HLA-D might be important in cellular recognition and graft-versus-host reactions (matching at HLA-D decreases the incidence and severity of graft-versus-host disease), and the Ir genes in the defense against infections. HLA-B and HLA-D loci are important markers in studies of disease susceptibility. HLA-B locus antigens HLA-B27 and HLA-B8 are frequently associated with arthritic or autoimmune disorders. HLA-D determinants have been found in association with multiple sclerosis and C2 deficiency (HLA-DW2); juvenile diabetes and Addison's disease (HLA-DW3) and adult type of rheumatoid arthritis (HLA-DW4).

Alleles

Linkage group HL-A-MLC-BF (properdin factor B). The site of the Bf locus at the immunogenetic linkage group on chromosome 6.

Genetic linkage between the HL-A and Bf loci could be confirmed in 43 families with 168 offspring. In 4 families, 5 recombinants out of 82 informative meiotic divisions were observed (r = 6.1%). The localisation of the Bf marker system was studied in 3 families with crossovers between HL-A and MLC. From these data the following map order of human chromosome 6 can be proposed: HL-A (1st locus) -- HL-A (2nd locus)--MLC-Bf---PGM(3). The fact that important components of the classical and alternate pathway of complement activation are governed by genes closely linked with HL-A and MLC loci leads to the proposition to include the Bf system into the Major Histocompatibility Complex in man.

Chromosome Mapping

Conceptual framework shifts in immunogenetics. II. Some notes on the Ag system.

Two Caucasian population materials totalling 530 individuals and 3,180 typing results are analyzed with regard to various combinations of the Ag(x, y, a1, d, c, g) factors. Superficially, both materials appear well aligned to each other and the contemporary (simple-complex) framework. However, when the same set of data are structuralized within a new (complex-simple) framework, the typing results for 12 of 362 or 3.3% of the Swiss and no less than 19 of 168 or 11.3% of the English samples are not compatible with the new framework specifying that the various anti-Ag reagents can be arranged in two 'inclusion groups'--the anti-Ag (y greater than d greater than c) and the anti-Ag (g greater than a1 greater than x) series.

England